Biology of Fungal Melanin

真菌黑色素的生物学

• 批准号: 7161747
• 负责人: Arturo Casadevall
• 金额: $ 33.04万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7161747
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Antibodies; Antibody Formation; Antifungal Agents; Binding; Biogenesis; Biological; Biological Process; Biology; Carbohydrates; Cells; Complex; Cryptococcus neoformans; Goals; Human; Immunology; Infection; Label; Laboratories; Laccase; Learning; Lipids; Melanins; Meningoencephalitis; Methods; Mus; Nature; Nucleic Acids; Pathogenesis; Patients; Pigments; Polymers; Process; Proteins; Role; Solutions; Structure; Techniques; Therapeutic; Virulence; Work; antimicrobial drug; cell growth; drug development; drug discovery; frontier; fungus; immunogenic; in vivo; insight; light scattering; microbial; novel; novel strategies; polymerization

Melanins are implicated in a variety of important biological processes yet they remain enigmatic polymers. For several oopportunistic pathogenic fungi including Cryptococcus neoformans, melanin synthesis is associated with virulence. C. neoformans is a major cause of meningoencephalitis in patients with AIDS. Melanin synthesis has been demonstrated to occur in C. neoformans during infection. The mechanism by which melanin contributes to virulene is poorly understood but may involve interference with host effector mechanisms. Apart from their importance in microbial pathogenesis, there is evidence that melanins reduce the efficacy of certain antifungal drugs implying that this pigment can be targeted for antimicrobial drug development. In fact, there is evidence that compounds which interfere with melanin polymerization can be therapeutic in murine experimental infection. Melanin is immunogenic and can elicit antibodies that protect against experimental C. neoformans infection. Antibodies to melanin cause cell growth arrest after binding to melanized cells indicating a novel mechanism of antibody action against fungi. The goals of this application are to better define the mechanisms by which melanin contributes to virulence, to investigate the role of antibody responses to melanin and laccase in host protection and correlate biological activity with structure by probing the structure of melanin using labeled substrates. Three aims are proposed: 1) to establish the mechanism by which melanin promotes the virulence of C. neoformans in vivo, 2) to establish the protective efficacy of antibody to C. neoformans melanin and laccase and the mechanism of antibody action, 3) to investigate the structure of C. neoformans melanin using biosynthetically incorporated substrates. It is anticipated that the work proposed here will provide important insights into the biology of melanin and in doing so highlight novel strategies for antimicrobial drug development.

黑色素与多种重要的生物过程有关，但它们仍然是个谜。 聚合物。对于包括新生隐球菌、黑色素在内的几种机会性致病真菌 合成与毒力有关。新生芽孢杆菌是#年脑膜脑炎的主要原因。 艾滋病患者。黑色素合成已被证明发生在新生葡萄球菌在 感染。黑色素对病毒素的作用机制知之甚少，但可能 涉及对宿主效应器机构的干扰。除了它们在微生物中的重要性 发病机制方面，有证据表明黑色素降低了某些抗真菌药物的疗效 这种色素可以作为抗微生物药物开发的靶点。事实上，有证据表明 干扰黑色素聚合的化合物可以在小鼠实验中用于治疗 感染。黑色素是免疫原性的，可以诱导抗体来保护实验中的C. 新生杆菌感染。黑色素抗体与黑化细胞结合后导致细胞生长停滞 提示了一种新的抗体抗真菌作用机制。此应用程序的目标是 更好地定义黑色素对毒力的作用机制，以研究 黑色素和漆酶在宿主保护中的抗体应答及其与生物活性的相关性 通过使用标记的底物探测黑色素的结构。提出了三个目标：1) 建立黑色素在体内促进新生葡萄球菌毒力的机制，2) 建立抗新生隐孢子虫黑素和漆酶抗体的保护作用 抗体作用机制，3)研究新生葡萄球菌黑色素的结构 生物合成结合的底物。预计这里提出的工作将提供 对黑色素生物学的重要见解，并在此过程中突出了针对 抗菌药物开发。